Unsaturated poly(ester-amide) biomaterials

ABSTRACT

Biodegradable poly(ester-amides) are synthesized from amino acids, diols and dicarboxylic acids where one or both of the diols and dicarboxylic acids contain unsaturation; e.g., from di-p-nitrophenyl dicarboxylates and p-toluenesulfonic acid salts of bis(alpha-amino acid) disesters of diols where one or both of the dicarboxylate and diol moieties contain unsaturation or from di-p-nitrophenyl dicarboxylates, and p-toluene-sulfonic acid salts of bis(alpha-amino acid) diesters of diols and p-toluenesulfonic acid salt of lysine ester where one or both of the dicarboxylate and diol moieties contain unsaturation. The polymers are useful as biodegradable carriers for drugs of other bioactive agents.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional PatentApplication No. 60/576,293, filed Jun. 3, 2004 and of U.S. ProvisionalPatent Application No. 60/638,385 filed Dec. 27, 2004, the whole of bothof which are incorporated herein by reference.

The invention was made at least in part with United States Governmentsupport under United States Department of Commerce Prime Grant Award No.99-27-07400 pursuant to a subagreement with The National Textile Center.The United States Government has certain rights in the invention.

TECHNICAL FIELD

This invention is directed at poly(ester-amide) biomaterials useful asbiodegradable carriers for drugs or other bioactive agents.

BACKGROUND OF THE INVENTION

Poly(ester-amide)s (PEAs) are polymers synthesized from non-toxic aminoacids, diols and dicarboxylic acids and are composed of both ester andamide blocks. They have been widely studied because they combine thefavorable properties of both polyesters and polyamides, i.e., theypossess not only good biodegradability but also good mechanical andprocessing properties, e.g., thermal stability, tensile strength andmodulus. Amino acids, due to their abundant availability from naturalsources and the potential biodegradability of their derivatives undercertain enzymatic catalyzed conditions, have often been chosen as thesource for the amine group of the biodegradable poly(ester-amide)s. Ithas also been reported that the inclusion of phenylalanine in thebackbone of the PEAs can enhance their biodegradability in the presenceof chymotrypsin.

All PEAs reported in the literature contain saturated backbone bridgingstructures. See, for example, U.S. Pat. No. 6,503,538 B1. This meansthat the PEAs synthesized before now, have to be modified before otherchemicals can be reacted with them.

SUMMARY OF THE INVENTION

In the invention herein, PEAs are provided which have built-infunctional groups on PEA backbones, and these built-in functional groupscan react with other chemicals and lead to the incorporation ofadditional functional groups to expand the functionality of PEA furtherand are therefore ready for reaction with other chemicals includinghydrophilic moieties (to increase water solubility), drugs and otherbioactive agents, without the necessity of modification first.

In one embodiment the invention is directed at a polymer having thestructural formula:

wherein R¹ is selected from the group consisting of (C₂-C₂₀) alkyleneand (C₂-C₂₀) alkenylene; R³ is selected from the group consisting ofhydrogen, (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl and (C₆-C₁₀)aryl(C₁-C₆) alkyl; and R⁴ is selected from the group consisting of(C₂-C₂₀) alkylene, (C₂-C₂₀) alkenylene, and ((CH₂)_(r)O)_(q)-(C₂-C₂₀)alkylene where r is 2 or 3 and q ranges from 1 to 4, where at least oneof R¹ and R⁴ comprises a radical selected from the group consisting of(C₂-C₂₀) alkenylene; and n ranges from about 5 to about 150, e.g., fromabout 50 to 150.

In one alternative, R³ is CH₂Ph and the amino acid used in synthesis isL-phenylalanine.

In a second embodiment the invention is directed at a polymer having thestructural formula:

where m ranges from about 0.1 to about 0.9; p ranges from about 0.9 toabout 0.1; n ranges from about 5 to about 150, e.g., about 50 to about150, each R¹ is independently selected from the group consisting of(C₂-C₂₀ alkylene) and (C₂-C₂₀) alkenylene. R² is hydrogen or(C₆-C₁₀)aryl (C₁-C₆) alkyl or t-butyl or other protecting group; R³ isselected from the group consisting of hydrogen, (C₁-C₆) alkyl, (C₂-C₆)alkenyl, (C₂-C₆) alkynyl and (C₆-C₁₀) aryl (C₁-C₆) alkyl; and R⁴ isselected from the group consisting of (C₂-C₂₀) alkylene, (C₂-C₂₀)alkenylene, and ((CH₂)_(r)O)_(q)-(C₂-C₂₀) alkylene where r is 2 or 3 andq ranges from 1 to 4, where one R¹ and R⁴ or both R¹s and R⁴ or both R¹sbut not R⁴ or one R¹ and not R⁴ or R¹ but no R¹s, comprise a radicalselected from the group consisting of (C₂-C₂₀) alkenylene.

The term “alkylene” is used herein as a linear saturated divalent tohydrocarbon radical.

The term “alkenylene” is used herein to mean a divalent branched orunbranched hydrocarbon chain containing at least one double bond in themain chain or in a side chain.

The molecular weights and polydisperities herein are determined by gelpermeation chromatography using polystyrene standards. Moreparticularly, number and weight average molecular weights (M_(n) andM_(w)) are determined using a Model 510 gel permeation chromatograph(Water Associates, Inc., Milford, Mass.) equipped with a high-pressureliquid chromatographic pump, a Waters 486 UV detector and a Waters 2410differential refractive index detector. Tetrahydrofuran (THF) is used asthe eluant (1.0 mL/min). The polystyrene standards have a narrowmolecular weight distribution.

The polymers herein are denoted UPEAs (unsaturated poly(ester-amide)s).

The term “biodegradable” is used herein to mean capable of being brokendown by various enzymes such as trypsins, lipases and lysosomes in thenormal functioning of the human body and living organisms (e.g.,bacteria) and/or water environment.

The term “biomaterial” is used herein to mean a synthetic material usedto function in intimate contact with living tissue.

The term “bioactive agent” is used herein to mean agent for delivery tocells, tissues or organs for nutrient or therapeutic effects. Theseinclude, but are not limited to nutrients, pharmaceuticals, drugs,peptides and oligo nucleotides.

The term “about” as used herein is meant to encompass variations of+/−2%, e.g., +/−0.5% or +/−0.1%.

DETAILED DESCRIPTION

We turn now to the UPEAs of the structure (I) as described above.

The polymers of the working examples, are those of the structure (I)where

and/or (b) R⁴ is —CH₂—CH═CH—CH₂—. In the working examples, in caseswhere (a) is present and (b) is not present, R⁴ in (I) is —C₄H₈— or—C₆H₁₂—. In the working examples, in cases where (a) is not present and(b) is present, R¹ in (I) is —C₄H₈— or —C₈H₁₆—.

The UPEAs can be prepared by solution polycondensation of either (1)di-p-toluenesulfonic acid salts of bis(alpha-amino acid) diesters ofunsaturated diol and di-p-nitrophenyl ester of saturated dicarboxylicacid or (2) di-p-toluenesulfonic acid salts of bis(alpha-amino acid)diesters of saturated diol and di-nitrophenyl ester of unsaturateddicarboxylic acid or (3) di-p-toluenesulfonic acid salt ofbis(alpha-amino acid) diesters of unsaturated diol and di-nitrophenylester of unsaturated dicarboxylic acid.

Salts of p-toluenesulfonic acid are known for use in synthesizingpolymers containing amino acid residues. The aryl sulfonic acid saltsare used instead of the free base because the aryl sulfonic acid saltsof bis(alpha-amino acid) diesters are easily purified throughrecrystallization and render the amino groups as unreactive ammoniumtosylates throughout workup.

The di-p-nitrophenyl esters of unsaturated dicarboxylic acid can besynthesized from p-nitrophenol and unsaturated dicarboxylic acidchloride, e.g., by dissolving triethylamine and p-nitrophenol in acetoneand adding unsaturated dicarboxylic acid chloride dropwise with stirringat −78° C. and pouring into water to precipitate product. Suitable acidchlorides are dicarboxylic acyl chlorides including, for example,fumaric, maleic, mesaconic, citraconic, glutaconic, itaconic,ethenyl-butane dioic and 2-propenyl-butanedioic acid chlorides.

The di-p-toluenesulfonic acid salts of bis(alpha-amino acid) diesters ofunsaturated diol can be prepared by admixing amino acid, aryl sulfonicacid (e.g., p-toluenesulfonic acid monohydrate) and unsaturated diol intoluene, heating to reflux temperature, until water evolution isminimal, then cooling. The unsaturated diols include, for example,2-butene-1,4-diol and 1,18-octadec-9-en-diol.

Di-p-nitrophenyl esters of saturated dicarboxylic acid anddi-p-toluenesulfonic acid salts of bis(alpha-amino acid) diesters ofsaturated diol can be prepared as described in U.S. Pat. No. 6,503,538B1.

The first embodiment of the invention is supported by experiments andresults and conclusions set forth in Guo, K., et al., Journal of PolymerScience, Part A: Polymer Chemistry 43(7), 1463-1477 (Feb. 15, 2005), thewhole of which is incorporated herein by reference.

We turn now to the second embodiment of the invention herein.

The compounds (II) can be made in similar fashion to the compound (VII)of U.S. Pat. No. 6,503,538 except that R₄ of (III) of U.S. Pat. No.6,503,538 and/or R₁ of (V) of U.S. Pat. No. 6,503,538 is C₂-C₂₀alkenylene as described above. The reaction is carried out, for example,by adding dry triethylamine to a mixture of (III) and (IV) of U.S. Pat.No. 6,503,538 and (V) where at least one of (III) and (V) containsC₂-C₂₀ alkenylene in dry N,N-dimethylacetamide, at room temperature,then increasing the temperature to 80° C. and stirring for 16 hours,then cooling the reaction solution to room temperature, diluting withethanol, pouring into water, separating polymer, washing separatedpolymer with water, drying to about 30C under reduced pressure and thenpurifying up to negative test on p-nitrophenol and p-toluenesulfonate. Apreferred reactant (IV) is p-toluenesulfonic acid salt of L-lysinebenzyl ester. When the reactant (IV) is p-toluenesulfonic acid salt ofbenzyl ester, the benzyl ester protecting group is preferably removedfrom (II) to confer biodegradability, but it should not be removed byhydrogenolysis as in Example 22 of U.S. Pat. No. 6,503,538 becausehydrogenolysis would saturate the desired double bonds; rather thebenzyl ester group should be converted to an acid group by a methodwhich would preserve unsaturation, e.g., by treatment with fluoroaceticacid or gaseous HF. Alternatively, the lysine reactant (IV) can beprotected by protecting group different from benzyl which can be readilyremoved in the finished product while preserving unsaturation, e.g., thelysine reactant can be protected with t-butyl (i.e., the reactant can bet-butyl ester of lysine) and the t-butyl can be converted to H whilepreserving unsaturation by treatment of the product (II) with diluteacid.

For the cases where R⁴ is ((CH₂)_(r)O)_(q)—(C₂-C₂₀) alkylene,di-p-toluenesulfonic acid salt of bis(alpha-amino acid) diester of loweroligomer of ethylene glycol is used in place of di-p-toluenesulfonicacid salt of bi(alpha-amino acid) diester of saturated diol and can beprepared by substituting lower oligomer of ethylene glycol (e.g.,diethylene glycol, triethylene glycol, tetraethylene glycol orpentaethylene glycol) in place of diol in the synthesis of III describedin U.S. Pat. No. 6,503,538 B1.

For both embodiments the following hold:

Aminoxyl radical, e.g., 4-amino TEMPO can be attached usingcarbonyldiimidazol or suitable carbodiimide as a condensing agent.

Drugs or other bioactive agents, e.g., anti-inflammatory agent (e.g.,sirolimus) or antiproliferative drugs (e.g., paclitaxel), or biologic,or protein or cytokine, or oligonucleotide including antisenseoligonucleotide, or gene, or carbohydrate, or hormone can be attachedvia the double bond functionality.

Hydrophilicity can be imparted by bonding to poly(ethylene glycol)diacrylate.

Applications for the polymers of the invention include the following:

-   -   1. Copolymerization with other functional monomers or polymer        precursors (e.g., for pH-sensitive or temperature sensitive        blocks) to provide controllable biodegradability.    -   2. To conjugate biologically active compounds via the        unsaturated double bond(s) of a UPEA so the resulting UPEA has        biological activity.    -   3. Formation of UPEA-based hydrogels via crosslinking of        unsaturated double bonds of UPEA.    -   4. Providing drug carriers, e.g., via application 2 above or by        inclusion in hydrogel of application 3 above.    -   5. Substrates for tissue engineering.

The invention is illustrated by the following working examples:

WORKING EXAMPLE I

In this example, the synthesis and characterization of a series ofbiodegradable UPEAs of the first embodiment of the invention by thesolution polycondensation of two unsaturated monomers, di-p-nitrophenylfumarate (NF) and p-toluenesulfonic acid salt ofbis(L-phenylalanine)2-butene-1,4-diester (PBe), and four saturatedmonomers, namely p-toluenesulfonic acid salt of bis(L-phenylalanine)butane-1,4-diester (PB), p-toluenesulfonic acid salt ofbis(L-phenylalanine) hexane-1,6-diester (PH), di-p-nitrophenyl adipate(NA), and di-p-nitrophenyl sebacate (NS), are described. The effects ofreaction time, temperature, and different solvents on the molecularweights and molecular weight distributions (MWDs) of the resultantpolymers are considered.

NA and NS were prepared through the reaction of the correspondingdicarboxylic acyl chlorides with p-nitrophenol as described inKatsarava, R., et al., J. Polym. Sci., Part A: Polym. Chem. 37, 391-407(1999).

NF was synthesized from p-nitrophenol and fumaryl chloride (FC)according to a modification of conditions used for synthesis of NA andNS, as follows: A solution of triethylamine (0.0603 mol) andp-nitrophenol (0.0603 mol) in 100 mL of acetone was prepared at roomtemperature, and this solution was kept at −78° C. with dry ice andacetone. FC (0.03 mol, 3.2 mL) in 40 mL of acetone was then added to thechilled solution dropwise with stirring for 2 h at −78° C. and then withstirring at room temperature overnight. After that, the mixture waspoured into 800 mL of distilled water to precipitate the product, NF,which was filtered, washed thoroughly with distilled water, dried invacuo at 50° C., and finally purified by recrystallization fromacetonitrile three times.

(PBe), (PB) and (PH) were prepared as follows: L-Phenylalanine (0.132mol), p-toluenesulfonic acid monohydrate (0.132 mol), and diol (0.06mol) in 250 mL of toluene were placed in a flask equipped with aDean-Stark apparatus, a CaCl₂ drying tube, and a magnetic stirrer. Thesolid-liquid reaction mixture was heated to reflux for 16 h until 4.3 mL(0.24 mol) of water evolved. The reaction mixture was then cooled toroom temperature, filtered and dried in vacuo, and finally purified byrecrystallization three times. According to the type ofdi-p-toluenesulfonic acid salt of bis(L-phenylalanine) diestersynthesized, different solvents were used for recrystallization. Forexample, water and n-butanol were used as recrystallization media forthe di-p-toluenesulfonic acid salt of bis(L-phenylalanine)butane-1,4-diester (PB) and di-p-toluenesulfonic acid salt of bis(L-phenylalanine) 2-butene-1,4-diester (PBe), respectively. Water wasused as the recrystallization medium for (PH).

Five different UPEAs were prepared, two by solution polycondensation ofNF with PB and NF with PH and two by solution polymerization of PBe withNA and PBe with NS and one by solution polymerization of NF and PBe. Thecombinations used are set forth in Table 1 below: TABLE 1 MonomerCombination Monomer Containing C═C Obtained Polymer NF + PB NF FPB NF +PH NF FPH NF + PBe NF and PBe FPBe NS + PBe PBe SPBe NA + PBe PBe APBe

In the solution polycondensations, excess triethylamine was used as theacid receptor for p-toluenesulfonic acid during the polymerization toregenerate free amino groups in the di-p-toluenesulfonic acid saltmonomer. Polymerization took place in a homogeneous phase, and thepolymer obtained remained dissolved in the reaction solution, exceptthat the reaction solution of FPH became a gel-like mixture after acertain time (longer at room temperature and shorter at a hightemperature). The gel-like mixture that formed during FPH synthesis wasproved to be not a real gel because it could dissolve inhexafluoroisopropanol and m-cresol, the latter being used as the solventfor viscosity measurements.

An example of the synthesis of APBe via solution polycondensation isgiven to illustrate the details of the synthesis procedures.Triethylamine (0.31 mL, 2.2 mmol) was added dropwise to a mixture ofmonomers NA (1.0 mmol) and PBe (1.0 mmol) in 1.5 mL of dry DMA, and thesolution was heated to 60° C. with stirring until the completedissolution of the monomers. The reaction vial was then kept under aspecified temperature (25° C. or 70° C.) for predetermined durations(24, 48, 72, or 96 h) without stirring to determine the effects of thetemperature and reaction duration on the polymerization reaction. Theresulting solution was precipitated with cold ethyl acetate, filtered,extracted by ethyl acetate in a Soxhlet apparatus for 48 h, and finallydried in vacuo at 50° C.

Confirmation that APBe was formed having the structure

where x=2, was confirmed by FTIR and NMR spectral data.

The effects of type of solvent, reaction temperature and reactionsolvent, on reduced viscosity and molecular weight of UPEAs wereexamined.

We turn now to the effect of different solvents on SPBe and FPB productsformed. Three organic solvents were used, namely N-methyl pyrrolidone(NMP), N,N-dimethylformamide (DMF) and N,N-dimethylacetamide (DMA). Inall three solvents, the reaction proceeded homogeneously. FPB would notdissolve in tetrahydrofuran (THF) or other normal organic solvents formolecular weight and MWD measurements so no data was observed for thesefor FPB. The results are set forth in Table 2 below: TABLE 2 MolecularWeight Reduced Viscosity (kg/mol) Sample Solvent (dL/g) M_(n) M_(w)M_(w)/M_(n) SPBe1 NMP 0.37 10.7 16.4 1.54 SPBe2 DMF 0.48 17.5 25.1 1.43SPBe3 DMA 0.46 17.3 24.7 1.43 FPB1 NMP 0.36 — — — FPB2 DMF 0.43 — — —FPB3 DMA 0.47 — — —All the reaction were carried out at 700C for 48 h. The concentration ofthe reaction solution was 1.10 mol/L.

As shown in Table 2, SPBe obtained in DMF and SPBe obtained in DMA had asimilar molecular weight and reduced viscosity value, which were muchhigher than those of SPBe synthesized in NMP. SPBe prepared in NMP alsohad a wider MWD than those prepared in DMF and DMA. FPB obtained in DMAhad the highest reduced viscosity value of the FPB polymers synthesizedin DMA, NMP and DMF. NMP was consequently not a good solvent forpreparing high molecular weight UPEAs. When DMF was used as the solventfor FPB synthesis, the reaction solution became a gel-like mixture. Thisrestricted chain propagation during polycondensation and led to theformation of polymers of relatively lower molecular weights. Such a lessdesirable reaction condition was improved when DMA was used as thesolvent. Therefore, DMA was found to be the best solvent for the SPBeand FPB synthesis.

The effects of reaction temperature (25° C. or 70° C.) and reactiontimes (24, 48, 72, 96 h) determined at those temperatures on themolecular weight and reduced viscosity of SPBe products were determined.Results are set forth in Table 3 below: TABLE 3 25° C. 70° C. ReducedReduced Reaction Viscosity M_(n) M_(w) Viscosity M_(n) M_(w) Time (h)(dL/g) (kg/mol) (kg/mol) M_(w)/M_(n) (dL/g) (kg/mol) (kg/mol)M_(w)/M_(n) 24 0.37 14.0 22.6 1.61 0.50 17.5 25.5 1.45 48 0.44 13.4 21.51.60 0.46 17.3 24.7 1.43 72 0.45 15.1 25.5 1.68 0.39 14.1 19.5 1.38 960.57 16.8 28.5 1.70 0.56 20.5 29.7 1.45

As shown in Table 3, M_(n), M_(w) and reduced viscosity of SPBeincreased with reaction duration, whereas MWD had a relatively smallerincrease. A higher reaction temperature (70° C.) increased not only thepolymerization rate but also the molecular weights (M_(n) and M_(w)) andnot at the expense of the MWD. The MWDs of the polymer obtained at 70°C. (average 1.4) appeared to become narrower than that of thepolymerization conducted at room temperature (average 1.6) and were lessdependent on the reaction time. The molecular weights at 70° C. did notincrease with the reaction time as much as those at 25° C.

On the basis of these data, the polycondensation of UPEA wassubsequently optimized to be carried out in DMA at 70° C. for 48 h (fora reaction as complete as possible), unless otherwise specified.

Elemental analysis results are set forth in Table 4 below: TABLE 4Empirical Formula Calculated (%) Experimental (%) Sample Formula (g/mol)C H N C H N FPB (C₂₆H₂₈N₂O₆)_(n) 464.52n 67.23 6.08 6.03 66.69 6.00 6.03FPH (C₂₈H₃₂N₂O₆)_(n) 492.57n 68.28 6.55 5.69 67.02 6.43 5.56 FPBe(C₂₆H₂₆N₂O₆)_(n) 462.50n 67.52 5.67 6.06 65.86 5.62 5.92 APBe(C₂₈H₃₂N₂O₆)_(n) 492.57n 68.28 6.55 5.69 66.85 6.65 5.68 SPBe(C₃₂H₄₀N₂O₆)_(n) 548.68n 70.05 7.35 5.10 69.05 7.27 5.02

Fundamental properties of the synthesized UPEAs were determined and areset forth in Table 5 below: TABLE 5 Reduced Empirical Formula YieldViscosity M_(n) M_(w) T_(g) T_(m) (FW) (%) (dL/g)^(b) (kg/mol) (kg/mol)M_(w)/M_(n) (° C.) (° C.) FPB C₂₆H₂₈N₂O₆)_(n) [(464.53)_(n)] 86 0.43 — —— 103  ˜250 FPH C₂₈H₃₂N₂O₆)_(n) [(492.57)_(n)] 87 0.30 — — — 92 ˜216FPBe C₂₆H₂₆N₂O₆)_(n) [(462.50)_(n)] 74 0.35 — — — 109  ˜223 APBeC₂₈H₃₂N₂O₆)_(n) [(492.57)_(n)] 84 0.25 15.6 22.8 1.46 61 N/A^(c) SPBeC₃₂H₄₀N₂O₆)_(n) [(548.68)_(n)] 54 0.46 17.3 24.7 1.43 46 N/A^(c)^(a)Synthesis conditions: concentration 10 mol/L, temperature 70° C.,DMA solvent.^(b)Measured in m-cresol at 25° C. (concentration 0.25 g/dl).^(c)Polymer decomposed when the temperature was greater than 240° C.

The UPEAs had higher T_(g) than the corresponding saturated PEAs. Thiswas because these UPEAs had one or two C═C double bonds in everyrepeating unit of the molecules. Such a structure reduced theflexibility of the polymer molecules and increased the difficulty ofchain-segment movement (i.e., higher T_(g)).

For all five UPEAs, the location of the C═C double bond in the polymerbackbone had a profound effect on T_(g). FPBe, which had the C═C doublebond in both the diester and diamide parts and thus the highest polymerchain rigidity, had the highest T_(g) (109° C.). The UPEAs based only onfumaryl, FPB and FPH, had the C═C double bond in the diamide part; theC═C double bonds also conjugated with the two carbonyl groups andresulted in a higher ridigidity of the polymer backbone. Thebutenyl-based UPEAs, APBe and SPBe, had isolated C═C double bonds in thediester part only; also, the 2-butene-1,4-diol used in the monomersynthesis for APBe and SPBe was a cis/trans mixture, which created somefree volume that counteracted some of the rigid effect brought by C═Cdouble bonds on the polymer molecules. Therefore, APBe and SPBe had muchlower T_(g)'s than FPB and FPH.

On the other hand, the effect of the length of the methylene groups inthe repeating unit of UPEAs on T_(g) can best be illustrated by acomparison of the T_(g) data for APBe and SPBe or for FPB and FPH. Sucha comparison of T_(g) data indicated that those UPEAs with longer —CH₂—chain segments in their repeating units, such as SPBe and FPH, had lowerT_(g)'s and the T_(g) of SPBe was the lowest of all five UPEAs. Thisrelationship between T_(g) and the number of methylene groups in UPEAcan be explained by the flexibility of the UPEA chain: more methylenegroups in the UPEA backbone resulted in higher flexibility.

The difference in T_(g) (ΔT_(g)=6° C.) between FPBe and FPB wasattributed to their structural differences: FPBe has C═C double bonds inboth the diester and diamide parts, but FPB has a C═C bond in thediamide part only. This difference in T_(g) is much smaller than thedifference between FPBe and APBe (ΔT_(g)>40° C.). Therefore, the T_(g)'sof the synthesized UPEAs were effected more by the C═C bond located inthe diamide block than by that located in the diester block. This may beattributed to the conjugation effect between the C═C double bonds andthe carbonyl groups in the diamide part, which had a greater restrictionon the bond rotation of the polymers.

Because of their unsaturated structure and the conjugation effectbetween the C═C double bond and the carbonyl groups, the fumaryl-basedUPEAs (FPB, FPH, and FPBe) had much higher T_(m)'s than thecorresponding saturated PEA reported previously. APBe and SPBe did nothave T_(m)'s and decomposed when the temperature was greater than 240°C.; this means that they did not have a crystalline structure.

Solubilities determined for the UPEAs (50 mg samples) at roomtemperature (25° C.) in 10 solvents (1 mL) are set forth in Table 6below: TABLE 6 APBe SPBe FPB FPH FPBe H₂O − − − − − Formic Acid + + − −± Trifluoroethanol + + − − − DMF + + ± ± + DMSO + + + ± + THF + + − − −Methanol ± − − − − Ethyl acetate − − − − − Chloroform + + ± − − Acetone− − − − −^(a)+ soluble; − insoluble; ± partially soluble or swelling.

As indicated by Table 6, all the UPEAs were completely or partiallysoluble in DMSO and DMF but could not dissolve in water, ethyl acetate,or acetone. UPEAs with a single unsaturated bond in each repeatingdiester unit (e.g., SPBe and APBe) could also dissolve intrifluoroethanol, formic acid, THF, and chloroform. Among the fiveUPEAs, the fumaryl-based ones (FPB, FPBe, and FPH) had poorersolubility, and FPH had the poorest solubility, probably because of notonly the strong hydrogen bonds between the molecules (via the amidegroup) but also the conjugation effect between the C═C double bonds andcarbonyl groups, which did not exist in APBe and SPBe. FPH had thelongest —CH₂— chain in its diester part of the five UPEAs, and itresulted in the strongest intermolecular interaction, the highesthydrophobicity, and thus the poorest solubility. The higher solubilityof FPB in formic acid and DMF and that of FPH in DMSO were obtained at ahigher temperature (e.g., 70° C.).

Wide angle X-ray diffraction was carried out on the UPEAs. Fumaryl-basedUPEAs FPH and FPB had well-defined semicrystalline structures, whichexplained why FPH and FPB had obvious melting peaks, whereas FPBe had asmaller peak; the other two UPEAs with unsaturated bonds in the diestersegment (APBe and SPBe) did not have enough crystallinity and justdecomposed when heated above approximately 240° C. SPBe existed almostin an amorphous state, and this explains why SPBe had the bestsolubility in some organic solvents, in comparison with the other UPEAs.

The polymers were obtained in fairly good yields at 70° C. in 48 h withDMA as the solvent. The molecular weights (M_(n) and M_(w)) of SPBe andAPBe, as measured by GPC, ranged from 10 to 30 kg/mol, and they had arather narrow MWD of 1.40. The chemical structures of the UPEAs wereconfirmed by IR and NMR spectra. The UPEAs had higher T_(g)'s thansaturated PEAs with similar backbone structures. The T_(g)'s of thesynthesized polymers were affected more by the C═C double bond locatedin the diamide part than by that in the diester part. The solubility ofthe polymers was poor in water and better in DMA and DMSO.

WORKING EXAMPLE II

A working example of the second embodiment is provided by substitutingp-toluenesulfonic acid salt of bis(L-phenylalanine) 2-butene-1,4-diesterfor (III) in Example 1 of U.S. Pat. No. 6,503,538 or by substitutingdi-p-nitrophenyl fumarate for (V) in Example 1 of U.S. Pat. No.6,503,538 or by substituting p-toluenesulfonic acid salt ofbis(L-phenylalanine) 2-butene-1,4-diester for (III) in Example 1 of U.S.Pat. No. 6,503,538 and also substituting di-p-nitrophenyl fumarate for(V) in Example 1 of U.S. Pat. No. 6,503,538.

VARIATIONS

The foregoing description of the invention has been presented describingcertain operable and preferred embodiments. It is not intended that theinvention should be so limited since variations and modificationsthereof will be obvious to those skilled in the art, all of which arewithin the spirit and scope of the invention.

1. A polymer having the structural formula:

wherein R¹ is selected from the group consisting of (C₂-C₂₀) alkyleneand (C₂-C₂₀) alkenylene; R³ is selected from the group consisting ofhydrogen, (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl and (C₆-C₁₀)aryl(C₁-C₆) alkyl; and R⁴ is selected from the group consisting of(C₂-C₂₀) alkylene, (C₂-C₂₀) alkenylene, and ((CH₂)_(r)O)_(q)-(C₂-C₂₀)alkylene where r is 2 or 3 and q ranges from 1 to 4, where at least oneof R¹ and R⁴ comprises a radical selected from the group consisting of(C₂-C₂₀) alkenylene; and n ranges from about 5 to about
 150. 2. Thepolymer of claim 1 having the structural formula (I) wherein R³ isCH₂Ph.
 3. The polymer of claim 2 where


4. The polymer of claim 3 where R⁴ is —CH₂—CH═CH—CH₂—.
 5. The polymer ofclaim 2 where R⁴ is —CH₂—CH═CH—CH₂—.
 6. The polymer of claim 3 where R⁴is (CH₂)_(n) where n ranges from 2 to
 20. 7. The polymer of claim 3where R¹ is C₂H₄.
 8. The polymer of claim 5 where R¹ is —C₄H₈—.
 9. Thepolymer of claim 5 where R¹ is —C₈H₁₆—.
 10. A polymer having thestructural formula:

where m ranges from about 0.1 to about 0.9; p ranges from about 0.9 toabout 0.1; n ranges from about 5 to about 150, each R¹ is independentlyselected from the group consisting of (C₂-C₂₀ alkylene), and (C₂-C₂₀)alkenylene; R² is hydrogen or (C₆-C₁₀)aryl (C₁-C₆) alkyl or t-butyl orother protecting group; R³ is selected from the group consisting ofhydrogen, (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl and (C₆-C₁₀)aryl (C₁-C₆) alkyl; and R⁴ is selected from the group consisting of(C₂-C₂₀) alkylene, (C₂-C₂₀) alkenylene, and ((CH₂)_(r)O)_(q)-(C₂-C₂₀)alkylene where r is 2 or 3 and q ranges from 1 to 4, where one R¹ and R⁴or both R¹s and R⁴ or both R¹s but not R⁴ or one R¹ and not R⁴ or R⁴ butno R¹s comprise a radical selected from the group consisting of (C₂-C₂₀)alkenylene.
 11. The polymer of claim 10 where in (II), R² and R³ areboth CH₂Ph.
 12. The polymer of claim 11 where


13. The polymer of claim 12 where R⁴ is —CH₂—CH═CH—CH₂—.
 14. The polymerof claim 11 where R⁴ is —CH₂—CH═CH—CH₂—.
 15. The polymer of claim 12where R⁴ is (CH₂)_(n) where n ranges from 2 to
 20. 16. The polymer ofclaim 14 where R¹ is —C₂H₄.
 17. The polymer of claim 14 where R¹ is—C₄H₈—.
 18. The polymer of claim 14 where R¹ is —C₈H₁₆—.